How cells communicate to coordinate their growth is a fundamental question in biology that is important to many aspects of medicine and health, including organ regeneration and transplantation, stem cell biology, and cancer. Here we address how a signaling pathway we recently uncovered functions during competitive interactions between cells in developing and remodeling tissues, in which normally viable cells are killed and eliminated when they grow next to winner cells with higher metabolic rates. We propose experiments in Drosophila to take advantage of the powerful genetic and molecular tools available, which are unparalleled in higher animals. We will use genetic analysis of mutants, somatic clonal techniques, and molecular analysis to achieve two specific aims: Aim 1, to investigate the mechanistic role of the signaling pathway in loser cells and discover target genes of the pathway that function as effectors of cell competition, and Aim 2, to determine how a putative ligand mediates communication between loser and winner cells and leads to activation of the signaling pathway in loser cells. These studies will reveal mechanisms underlying interactions between cells in growing epithelia that may be valuable for improving the health and care of humans. In addition, they will expand our understanding of fundamental aspects of cell-cell communication during growth. PUBLIC HEALTH RELEVANCE: Our previous work using Drosophila as a model system has demonstrated that competition is induced between neighboring cells when they grow with different metabolic rates. This process ensures tissue plasticity during growth and development. Our recent experiments have implicated a novel signaling pathway in the competition process, and here we aim to use the unparalleled power of Drosophila molecular genetics to understand its role in the cellular events involved in competition, such as overgrowth, cell death and cell-cell communication. Cell competition has remarkable similarities to the early stages of cancer, thus we anticipate that this work will aid in the identification of markers distinguishing early cancer cells from their wildtype neighbors. In addition, it will enhance our knowledge of mechanisms of tissue plasticity and fitness selection. Furthermore, our understanding of the basic biological properties of cell communication during growth will be expanded.